Drug therapies for HIV infection suffer from the appearance of resistant viral strains. In these organisms, an enzyme which is the drug target has an altered sequence. As a result, it binds drug less effectively. Conformational flexibility in non-nucleoside inhibitors of HIV-1 reverse transcriptase (RT) is thought to contribute to a broader spectrum of activity; in molecular terms, a single drug binds wild type enzyme in one conformation and "mutant" enzyme in another. An increase in entropy of binding which is associated with molecular flexibility may be acceptable if binding is very tight. The goals of this R-21 proposal are - to prepare a series of molecules designed to be "two-site" inhibitors of HIV RT. In these molecules, a nucleoside moiety and a non-nucleoside inhibitor moiety will be tethered so that each can, in principle, occupy its binding site on the enzyme. - to demonstrate that at least one of these targets is an extremely tight binder. Successful achievement of these goals will position us - to expand the library of "two-site inhibitors" - to demonstrate that at least one of these occupies both target sites - to determine whether treatment of wild-type virus with any of the "two-site" inhibitors leads to the appearance of resistant strains. -to modify the structures of lead compounds, if necessary, in order to minimize the appearance of resistant strains.